Liquid, and especially concentrated liquid pharmaceutical compositions containing acetaminophen in solution offer several advantages over solid compositions. Liquids are easy to swallow and provide an excellent vehicle for the uniform delivery of pharmaceutical actives. Moreover, liquids provide a rapid onset of pharmacologic action, since the composition does not first have to disintegrate and dissolve in the gastrointestinal tract. Likewise, concentrated liquid compositions offer certain distinct advantages. These compositions are ideally suited for incorporation into easy-to-swallow soft, flexible capsules. Encapsulation of this nature permits the accurate and uniform delivery of unit dose amounts of a pharmaceutical active, encompassing even those instances where relatively small amounts of a pharmaceutical active are to be delivered. In addition, soft gelatin capsules are aesthetically appealing (especially when filled with a transparent liquid) and can be manufactured in a wide variety of sizes, shapes, and colors.
These advantages notwithstanding, it is often difficult to prepare such compositions using the desired pharmaceutical active however. Acetaminophen is poorly soluble and, therefore, require relatively large volumes of solvent for dissolution, resulting in impractically large doses. Also, encapsulating such large volumes into easy-to-swallow gelatin capsules presents obvious difficulties, suggesting the immediate importance of concentrated liquid compositions. Furthermore, the situation becomes even more complicated when multiple pharmaceutical actives are involved.
The most frequently used approach to this solubility problem is to force solubility into small volumes of solvent by means of a step-wise process incorporating heat. This step-wise process consists of dissolving the acetaminophen in polyethylene glycol and polyvinylpyrrolidone with heat, followed by the addition of any additional pharmaceutical actives. Because the resultant concentrated liquid (or fill) is a supersaturated solution of the acetaminophen, it is even more difficult to increase the resultant composition's concentration of acetaminophen.
The present inventor has discovered that by using a specific acetaminophen formed by adding a Beckman rearrangement catalyst to 4-hydroxyacetophenone oxime, said catalyst having an electrophilic carbon atom at which said catalyst reacts with said oxime provides compositions having improved stability.
It is, therefore, an object of the present invention to provide such compositions containing acetaminophen having improved stability. A further object of the present invention is to enhance stability of the resultant composition by reducing the tendency of the acetaminophen to precipitate out of solution. These and other objects of this invention will become apparent in light of the following discussion.